Examining Neurocircuit and Behavioral Effects in a Developmental Model for Indirect Pathway Hypofunction

检查间接通路功能障碍发育模型中的神经回路和行为效应

• 批准号: 10449771
• 负责人: Pedro Rabelo Olivetti
• 金额: $ 19.55万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449771
• 关键词: ADORA2A gene; Academic Medical Centers; Address; Adult; Affect; Agonist; Animals; Antipsychotic Agents; Attention; Balsams; Basal Ganglia; Behavior; Behavioral; Binding; Biological Models; Clozapine; Cognition; Cognitive; Cognitive deficits; Computer Analysis; Corpus striatum structure; Coupled; Cre driver; Data; Data Set; Development; Development Plans; Devices; Disease; Doctor of Philosophy; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Early Intervention; Etiology; Fiber; Foundations; Functional disorder; Future; Globus Pallidus; Goals; Head; Human; Image; Impaired cognition; Injections; Institutes; K-Series Research Career Programs; Laboratory Research; Lead; Life; Ligands; Link; Measurement; Measures; Medial; Mental disorders; Mentorship; Methods; Midbrain structure; Modeling; Motivation; Mus; Neonatal; Neurodevelopmental Disorder; Neurons; Neurosciences; New York; Nucleus Accumbens; Oxides; Pathway interactions; Patients; Phenotype; Photometry; Physicians; Play; Prefrontal Cortex; Preventive; Psychiatry; Psychoses; Psychotic Disorders; Receptor Signaling; Research; Research Personnel; Resistance; Rewards; Risk; Risk Factors; Role; Schizophrenia; Scientist; Shapes; Short-Term Memory; Signal Transduction; Stimulus; Substantia nigra structure; Symptoms; Synapses; System; Testing; Thinking; Time; Training; Universities; Up-Regulation; Ventral Tegmental Area; Viral; Virus; Work; antagonist; base; calcium indicator; career; career development; cognitive performance; cognitive testing; complex data; design; dopamine system; dopaminergic neuron; experimental study; human imaging; imaging study; improved; in vivo; insight; mature animal; microendoscopy; motivated behavior; neonatal brain; neonatal mice; neuropsychiatric disorder; neurotransmitter release; novel; overexpression; pars compacta; postnatal; receptor; receptor function; receptor upregulation; response; sensor; willingness

Project Summary I am an MD/PhD physician-scientist trained in psychiatry and neuroscience. My career goal is to become an independent neuroscience investigator devoted to a mechanistic understanding the long-term contributions of altered neurodevelopmental trajectories to neuropsychiatric disorders. I ultimately hope that discoveries made in my lab will generate new ways to assess risk factors during early life, as well as spur novel treatment and preventive approaches to neuropsychiatric disorders—in particular schizophrenia (SCZ), a devastating disorder in which development is thought to play an important but poorly understood role. I have designed a research plan that is integrated with my training objectives and career development plan, and will propel me towards scientific independence. Using the mouse as my model system, the questions I intend to address in this K08 proposal are centered on how striatal pathway-specific perturbations during basal ganglia (BG) circuit formation can shape developmental trajectories and alter the character of BG circuit computations with lasting behavioral consequences. Dysfunctions in dopamine (DA) signaling in the striatum and prefrontal cortex have long been associated with motivational and cognitive deficits in humans. In the striatum, increased expression of dopamine D2 receptors (D2Rs) in indirect pathway neurons have been implicated in the etiology of SCZ, but developmental mechanisms remain limited4-7. Mouse studies have shown that a non-pathway-specific developmental D2R overexpression led to behavioral deficits that were associated with altered DA signaling from the midbrain on striatum and prefrontal cortex16, 17, 20, 47. Meanwhile, early postnatal chemogenetic inhibition (with hM4D activation) of indirect pathway resulted in restructuring of corticostriatal synapses lasting for at least ten days19— suggesting a developmental window for corticostriatal wiring that may shape behaviors dependent on this circuitry. In this K08 proposal, I will address these questions with two Specific Aims. In Aim 1, I will test the hypothesis that transiently inhibiting striatal indirect pathway neurons during an early postnatal developmental window will result in decreased motivation and impaired cognitive performance in adult mice. I have developed a stereotaxic neonatal adaptor that improves regional targeting with viral vectors1. Preliminary data suggest a developmental effect on motivated behavior. In Aim 2, I will test the hypothesis that the developmental manipulation leads to persistent circuit-level changes affecting long-term DA release in adults, possibly by altering midbrain neuronal activity. I will record real-time striatal DA release dynamics in freely behaving mice by fiberphotometry (FP). To examine midbrain neuronal activity in vivo, I propose Ca2+ imaging experiments in freely behaving animals, using a virally-encoded Ca2+ indicator, GCaMP6f, in midbrain neurons. I will conduct this project at the New York State Psychiatric Institute and Columbia University under the mentorship team of Drs. Christoph Kellendonk, Peter Balsam, Mark Ansorge, René Hen, Joshua Berke, and Jonathan Javitch. Through the completion of the training goals delineated in this career development award proposal, I will be prepared to transition into scientific independence leading a research laboratory in an academic medical center.

项目摘要 我是受过精神病学和神经科学训练的医学博士/博士学位科学家。我的职业目标是成为独立 神经科学研究者致力于理解改变的长期贡献 神经发达的神经精神疾病轨迹。我最终希望我的实验室发现的发现 产生新的方法来评估早期生命期间的危险因素，并刺激新颖的治疗方法和预防方法 神经精神疾病，特别是精神分裂症（SCZ），一种毁灭性疾病，其中被认为是发展的 扮演重要但理解不佳的角色。我设计了一个与我的培训相结合的研究计划 目标和职业发展计划，并将我推动我发展科学独立性。将鼠标用作我的 模型系统，我打算在此K08提案中解决的问题集中在纹状体途径特定方面 基底神经节（BG）电路形成期间的扰动可以塑造发展轨迹并改变 BG电路计算具有持久的行为后果。纹状体中多巴胺（DA）信号的功能障碍 长期以来，前额叶皮层与人类的动机和认知定义有关。在纹状体中， 在病因中隐含了间接途径神经元中多巴胺D2受体（D2R）的表达增加 SCZ，但发展机制仍然有限4-7。小鼠的研究表明，非道路特异性 发育D2R的过表达导致行为定义了与来自DA信号的改变有关的行为。 中脑在纹状体和额叶前皮质16、17、20、47。同时，早期产后化学抑制（使用HM4D 激活）间接途径导致持续至少十天的皮质纹状体突触恢复 - 提出了一个可能塑造基于该电路的行为的皮质纹状体接线的发育窗口。在这个 K08提案，我将以两个具体的目的解决这些问题。在AIM 1中，我将测试瞬时的假设 在产后早期发育窗口期间抑制纹状体间接途径神经元将导致下降 成年小鼠的动机和认知表现受损。我已经开发了一个立体定义的新生儿适配器 通过病毒载体改善区域靶向1。初步数据表明对动机行为产生了发展影响。在 AIM 2，我将检验以下假设：发育操作会导致持续的电路级变化影响 成人长期释放，通过改变中脑神经元活性。我将录制实时纹状体DA发行 通过纤维测定法（FP）进行自由行为小鼠的动力学。要检查体内脑神经元活性，我提出了CA2+ 使用病毒编码的Ca2+指示剂GCAMP6F在中脑神经元中进行的自由行为动物的成像实验。 我将在Mentalship团队下在纽约州精神病学研究所和哥伦比亚大学进行该项目 博士。 Christoph Kellendonk，Peter Balsam，Mark Ansorge，RenéHen，Joshua Berke和Jonathan Javitch。通过 在本职业发展奖提案中划定的培训目标的完成，我将准备过渡到 科学独立性在学术医学中心领导研究实验室。